Subclinical thyroid disorders: still a matter of controversy

1
Subclinical thyroid disorders still a matter of
controversy
Simon HS Pearce
2
Plan
Background Subclinical hypothyroidism -Vasc
ular risk Subclinical hyperthyroidism -Underst
and the pathophysiology -Approach to Management
3
What is normal?
16 healthy individuals, having monthly TFTs for
1 year People stick to their own reference
interval Extrapolating to Free T4 values
-setpoint /- 2.5 pmol/l My normal range is
different from yours
Andersen et al. JCEM 2002
4
TSH in centenarians and offspring
? 232 Ashkenazim, age 97 o 366 of offspring, age
69 ? 177 age-matched controls
Atzmon et al. JCEM 2009
5
(No Transcript)
6
Possible mechanisms
Dyslipidaemia Cardiac systolic diastolic
dysfunction Hypertension Endothelial
dysfunction Hypercoagulability

7
Hard outcomes

• Rotterdam Heart Study
• Community-based cross sectional survey
• 1149 women (mean age 69 /-7 yrs)
• 10.8 had subclinical hypothyroidism (TSHgt4.0,
  N FT4)
• Odds ratio for MI 2.3 (CI 1.3-4.0)
• OR for aortic atherosclerosis 1.7 (1.1-2.6)
• Population attributable risk of ?TSH to MI
  estimated to be 14
• N.B. Diabetes 14, Smoking 15

Hak et al. Ann Intern Med 2000132 270
8
Meta-summary of meta-analyses
Relative risks (5-95 confidence intervals)
Author Number Cardiovascular events Cardiovascular mortality All cause mortality
Singh 2008 13,267 1.53 (1.311.79) 1.28 (1.021.60) 1.12 (0.99-1.26)
Ochs 2008 14,449 1.20 (0.97-1.49) 1.18 (0.98-1.42) 1.12 (0.99-1.26)
Haentjens 2008 14,619 NI NI 1.22 (0.95-1.57)
Razvi 2008 29,022 1.23 (1.02 1.48) 1.09 (0.84 1.41) NI
Rodondi 2010 55,287 1.18 (0.99- 1.42) 1.14 (0.99- 1.32) 1.09 (0.96-1.24)
Thvilum 2012 35,740 NI NI 1.17 (1.00-1.37)
9
Meta-summary of meta-analyses
Relative risks (5-95 confidence intervals)
Author Number Cardiovascular events Cardiovascular mortality All cause mortality
Singh 2008 13,267 1.53 (1.311.79) 1.28 (1.021.60) 1.12 (0.99-1.26)
Ochs 2008 14,449 1.20 (0.97-1.49) 1.18 (0.98-1.42) 1.12 (0.99-1.26)
Haentjens 2008 14,619 NI NI 1.22 (0.95-1.57)
Razvi 2008 29,022 1.23 (1.02 1.48) 1.09 (0.84 1.41) NI
Rodondi 2010 55,287 1.18 (0.99- 1.42) 1.14 (0.99- 1.32) 1.09 (0.96-1.24)
Thvilum 2012 35,740 NI NI 1.17 (1.00-1.37)
10
All cause mortality in SCH
M Thvilum, F Brandt, TH Brix L Hegedus. Nat
Rev Endocrinol 2012
11
Janus response Age
Thanks to Stefano Mariotti David Cooper
12
Meta-analysis

• Performed by Salman Razvi/ Abdul Shakoor
• Longitudinal or cross sectional studies of
  independent community-based subjects
• 14 studies fitted stringent criteria
• 2,531 SCH participants
• 26,491 euthyroid individuals
• Divided studies according to age of inclusion
• lt65 yr vs 65 and above median 60 74 yr

13
IHD prevalence in cross-sectional studies of SCH
euthyroid controls
14
IHD incidence in longitudinal studies of SCH
euthyroid controls
15
Cardiovascular mortality in longitudinal studies
of SCH euthyroid controls
16
Summary

• Prevalent and incident IHD, and IHD mortality is
  increased in SCH compared to euthyroid population
• Evidence of increased IHD confined to studies
  that have included people aged less than 65 years

Razvi et al. JCEM 2008
17
Patient-level analysis

• 55,287 participants 3,450 with SCH (6.2)
• Information derived from 11 studies
• 9664 deaths 2168 from CHD
• SCH defined as TSH 4.5-19.99 mU/l (N FT4)

Rodondi et al. JAMA 2010
18
Patient-level analysis TSH
19
Patient-level analysis TSH
20
Patient-level analysis Age
21
Interim Summary

• Meta-analysis with many thousands of patient
  events shows vascular death is associated with
  SCH
• Effect is greater at higher TSH levels, reaching
  significance at TSH of 7.0 mU and above
• Effect is attenuated at older ages

22
UK General Practice Research Database

• Primary care resource linking 10 million patient
  records, labs, prescriptions death certificates
• During 2001 there were 322,291 TSH measurements
• Identified 4,735 people gt40 yrs with TSH 5.0-
  10.0 mU/l, normal FT4
• Excluded individuals on L-T4, ATDs, previous
  thyroid disease, previous IHD, stroke, other
  vascular disease

Razvi S et al. Arch Intern Med 2012
23
UK General Practice Research Database

• Participants followed until March 2008 (median
  7.6 yrs)
• People aged 40- 70 yrs (n3093) and gt70 yrs
  (n1642)
• 52.9 and 49.9 were treated with L-thyroxine
  during follow up (Primary Care decision)
• Analysed outcomes for incident IHD, vascular and
  all cause mortality over follow up period (Cox
  regression MVA)

24
L-Thyroxine treated group
94 of people continued to take L-T4 Median
dose 75µg (12.5-175 µg) daily
25
Untreated group
1.3 developed overt hypothyroidism -(TSH
gt10, or ? FT4) 58 remained with elevated
TSH 38 reverted to euthyroidism 2.5
developed low TSH
26
Baseline characteristics
40-70 yrs 40-70 yrs gt70 yrs gt70 yrs
Untreated L-T4 Rx Untreated L-T4 Rx
Number 1459 1634 823 819
Age 55.9 8.3 55.9 8.4 79.9 6.5 79.4 6.2
Females 82.5 87.4 75.6 84.6
Serum TSH (mU/l) 6.3 1.3 6.7 1.4 6.3 1.2 6.8 1.4
Serum FT4 (pM) 13.4 4.4 12.9 3.0 14.6 4.4 13.9 3.4
BMI (Kg/m2) 27.8 5.9 28.1 6.2 25.4 4.6 26.3 5.1
Systolic BP (mmHg) 136.5 20.0 135.2 19.3 149.4 23.5 149.4 22.0
T Cholesterol (mM) 5.86 1.34 5.82 1.21 5.93 1.36 5.95 1.25
Diabetes 18.0 18.1 26.9 26.6
Smokers (current) 18.3 17.9 10.9 10.1
Deprivation index 17.5 16.75 15.86 16.58
GP contacts/yr 1.2 1.3 2.3 2.4
27
Fatal non-fatal vascular events 40-70 yrs
HR 0.61 (0.39- 0.95) p0.02
28
All cause mortality40-70 yrs
HR 0.36 (0.19 0.66) plt0.001
29
Fatal non-fatal IHD events gt70 yrs
HR 0.99 (0.59- 1.33) p0.56
30
All cause mortalitygt70 yrs
HR 0.71 (0.56 1.08) p0.11
31
Event rate stratified by age
LT4 vs untreated Fatal non fatal CV events
32
Degree of serum TSH elevation
Median serum TSH 6.6 mU/l Reference group
(HR1) is untreated patients
Hazard Ratio for vascular events Hazard Ratio for vascular events P value for trend
TSH 6.6 or less TSH gt 6.6
40-70 yrs 0.62 (0.39-0.96) 0.41(0.26-0.81) 0.007
gt70 yrs 1.02 (0.66-1.82) 1.19 (0.74-1.80) NS
Razvi et al. Arch Intern Med 2012
33
Atrial fibrillation
Hazard Ratio for AF/ month L-T4 exposure 5-95 CI
40-70 yrs 0.998 0.995- 1.001
gt70 yrs 1.000 0.999- 1.001
34
Summary

• L-T4 treatment of SCH was associated with a
  lower CV mortality and CV event rate in patients
  lt70 yrs
• Importantly, L-T4 treatment was not associated
  with AF
• Not an RCT study, but represents outcome of
  real-life practice

Razvi et al. Arch Intern Med 2012
35
Who should we treat?

• Pregnant patients, or planning pregnancy
• Patients with serum TSH gt 10.0 mU/l

36
Who should we consider treating?

• Symptoms or signs of hypothyroidism
• Age less than 70 yrs
• TSH gt7.0 mU/l
• Goitre
• High vascular risk including
• Ischaemic heart disease
• Diabetes
• Dyslipidaemia

37
380 attendees at ITC 2010 Electronic voting
system Female, serum TSH 6.8
Pearce, Wemeau, Vaisman. Eur Thyroid J 2012
38
Subclinical hyperthyroidism
39
What is normal in extreme old age?
Age-related decline in median TSH levels (ill
people excluded)
Mariotti et al. JCEM 1993
40
What is normal in extreme old age?
Age related decline in T3 levels (ill people
excluded) FT4 (and TT4) levels remain constant
Mariotti et al. JCEM 1993
41
Magri et al. 2002
42
Change to function of HPT axis

• Reduced hepatic thyroid hormone clearance
• -glucuronidation, sulfation
• Reduced T4 to T3 conversion
• Reduced type 1 deiodinase activity
• Blunted diurnal TSH secretion
• Flattened TSH response to TRH

43
Subclinical Hyperthyroidism
44
Degrees of hyperthyroidism
45
Degrees of hyperthyroidism
12 months follow up
76 returned to normal
87 remained lt0.1
Parle JV et al. 1991 Clin Endo
46
Prevalence Both grades 1-3 of elderly
subjects in NHANESIII 2.1 in Colorado
Health Fair study Suppressed TSH 0.7 of
TFTs from people not on T4 at RVI
NHANES III
47
Should we be concerned about subclinical
hyperthyroidism?
Evidence
48
Small risk of progressionto overt disease

• Parle et al. 1991 TSH lt0.1 2/ year
• Wiersinga et al. 1995 5/ year
• Pirich et al. 2000 TSH lt0.1 7/ year
• Schouten et al. 2011 5-8/ year
• Rosario et al. 2010 TSH 0.1-0.4 1 /year

49
AF in Framingham survey
Sawin et al. NEJM 1994
50
Cardiovascular Health Study
3233 US community dwelling individuals over 65,
mean age 73 AF rate 2.0 (CI 1.3-3.0) in Sub
Hyper
Cappola et al. JAMA 2006
51
Overall survival Circulatory survival
Community-living gt60 year olds overt thyroid
disease excluded
Parle et al. Lancet 2001
52
TSH lt0.3mU/l
Normal TSH
TSHgt4.8mU/l
n558 Birth cohort design All 85 yrs at
baseline Leiden, NL Hazard Ratio per 2.71
mU/l increase in TSH is 0.77 (0.63-0.94)
Gussekloo et al. JAMA 2004 2922591
53
CHD (fatal non-fatal)
20 yr follow up of population survey, Western
Australia n2108 Mean age 51 (17-89) subclin
hypER 1.8 No effect of subclinical
hyperthyroidism
Busselton Health Study Arch Intern Med 2005
54
Meta-analysis of 10 cohort studies
52,000 participants (2188 with SH)
Collet et al. Arch Intern Med 2012
55
Summary of observational studies
Increased incidence of AF in SH Increased
vascular mortality in SH groups in most, but not
all studies SH sounds like bad news for your
heart
56
Functional cardiac effects of subclinical
hyperthyroidism

• Resting tachycardia
• LV hypertrophy
• Increase LV mass index
• Increase cardiac workload
• Diastolic dysfunction (impaired relaxation)
• Increased systolic function at rest
• Impaired systolic response to excercise

Biondi, Kahaly, Klein and others
57
Non-vascular effects of SH
Effect Reference
Bone mineral density Decreased Mudde 1994, Faber 1998, Tauchmanovà et al. 2004
Fracture Increased x3 4.5 hip vertebral Bauer et al. 2001
Muscle strength Knee extension Decreased by 30 Brennan et al. 2006
Dementia Increased x 3.5 Kalmijn et al. 2000
58
OK Subclinical hyperthyroidism is bad
newsLets treat everybody and make them better
59
No evidence that treatment is effective
Problem?
60
RCTs of radioiodine in SH

• Dutch trial poor recruitment rate, other
  factors Trial terminated 2005
• UK Trial poor recruitment rate (lt 10 of SH
  patients agreed to randomisation). Trial
  terminated 2009
• French trial Prof. B Goichot,- ongoing- AF as
  primary endpoint (target 300 patients)

61
No evidence that treatment is effective
Problem?
62
Problems with study designs

• Participant cohort defined by a single TSH
  measurement
• AF and mortality followed subsequently
• Many subjects (gt50) will have subsequently
  normalised TSH levels during follow up
• How to interpret adverse outcome of low TSH/
  Subclinical hyperthyroidism group?

63
Formulation 1

• Low TSH represents true endogenous
  hyperthyroidism
• Adverse cardiac events AF are an expected
  consequence of excess thyroid hormones
• Need to treat for hyperthyroidism

64
Formulation 2

• Low TSH represents an effect of ageing and
  reduced turnover of pituitary-thyroid axis
  (biomarker for age)
• Decreased hepatic thyroid hormone clearance,
  blunted diurnal TSH secretion flattened TSH
  response to TRH with ageing
• Adverse cardiac events AF ( OP dementia)
  simply are consequences of biological age
• No need to treat for hyperthyroidism

65
Formulation 1.5

• Both the previous suggestions are true
• Adverse cardiac effects are due to excess thyroid
  hormones in some
• In others, low TSH is a biomarker for aging
  hence associated with poor outcome
• Need to distinguish between these two groups to
  treat some for hyperthyroidism

66
Cardiovascular Health Study
TSH mU/l N AF rate/1000 pt yrs Hazard ratio (5-95 CI)
Euthyroid 2502 31 1.00 (ref)
lt0.44 47 67 1.98 (1.29-3.03)
0.1-0.44 40 59 1.85 (1.14-3.00)

• AF rate little different between
• grade I and grade II SH

Cappola et al. 2006
67
TEARS study
2004 patients with SH vs 10,111 controls 2
TSH measurements 4/12 apart Median follow up
5.6 yrs
Vadiveloo et al. JCEM 2011
68
What to do?
Observe 3 to 6 months Look out for drug/
contrast effects -Thyroxine -Opiates -Glucocort
icoid -Metformin -L-DOPA -Amiodarone -CT
contrast (Iopaque)
69
What to do?

• TSH lt0.1 mU/l
• Age lt75
• Symptoms, goitre
• Above median FT3, FT4
• ve Antibodies, nuclide scan
• Complications, AF

TSH 0.1-0.4 mU/l Age gt75 No symptoms
Below median FT3, FT4 -ve Antibodies, scan
No complications
70
Algorithm
Rare causes Pituitary disease Tumour hCG
Repeat testing May need investigations
Maybe yearly re-testing Maybe never re-test
Mitchell Pearce. Clin Endo 2010
71
There is no reason to treat a patient with
subclinical hyperthyroidism for thyrotoxicosis,
provided they are in sinus rhythm
Peer opinion BTA Survey
Vaidya B et al. Clin Endo 2008
72
Summary

• Low serum TSH is common in advanced age
• In many, it is transient in others may be a
  feature of ageing
• The minority will require treatment
• Large evidence vacuum remains

73
Dr. Salman RazviPerformed much of the hard work
74
Acknowledgements

• TRISH Investigators and Steering committee
• Amit Allahabadia Alison Mortimer
• Diana Elbourne, Jayne Franklyn, Malcolm
  Prentice, Graham Williams, Janis Hickey, Murray
  Stewart, Wilmar Wiersinga
• Newcastle Co-investigators
• Salman Razvi, Anna Mitchell, Joanna Collerton,
  Andrew Kingston 85 Core study team
• BTA survey Bijay Vaidya

Newcastle Healthcare Charity
75
The End